CN117164563A - 新型氧代嘧啶类化合物及其制备方法和用途 - Google Patents
新型氧代嘧啶类化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种式(Ⅰ)所示的化合物、其立体异构体、或药学上可接受的盐。本发明还提供了所述化合物、其立体异构体或药学上可接受的盐在制备治疗和/或预防与FⅪa受体相关的疾病的药物中的应用,尤其是在制备治疗和/或预防脑血管动脉疾病和/或外周动脉疾病药物中的应用,药效显著。
Description
技术领域
本发明涉及药物化学领域,具体涉及氧代吡啶类化合物或其盐、异构体、及其制备方法以及在制备治疗和/或预防与FⅪa受体相关的疾病的药物中的用途,尤其在制备治疗脑血管动脉疾病和/或外周动脉疾病等药物中的用途。
背景技术
血栓栓塞病是人类和动物在存活期间,由血管内形成的异常血凝块造成的疾病,临床上可能表现为心肌梗死、中风、深度静脉血栓(deepveinthrombosis,DVT)、肺栓塞、心房颤动和脑梗死等,每年夺走全球上千万人生命。凝血因子XI(FXI)是维持内源性途径所必需的一种血浆丝氨酸蛋白酶原,激活后生成活化的凝血因子XIa(FXIa),在凝血级联反应放大过程中发挥关键作用。因此,针对FXIa靶点的药物可阻断内源性途径并抑制凝血级联反应的放大,从而具有抗血栓形成的作用。
已报道的FXIa抑制剂主要包括单克隆抗体、反义寡核苷酸、化学小分子、多肽或蛋白及多肽模拟物等。目前,BMS与强生联合开发的milvexian已完成临床II期试验,结果显示具有较小的出血风险。BMS的静脉注射小分子FXIa抑制剂BMS-962122的临床I期试验已经完成,已暂停研发。日本小野公司研发的小分子口服FXIa抑制剂ONO-7684进入临床I期研究。Bayer研发的BAY-2433334已完成临床II期试验,成为目前最有前景的小分子FXIa抑制剂。单抗和反义寡核苷酸需要注射给药,且存在价格昂贵、起效慢和可能不易控制等不足,化学小分子具有相对较好的口服生物利用度和更好的患者依从性等优势。
因此,研发安全有效、特异性好和活性强的FXIa小分子抑制剂新药可能为弥补目前临床抗凝抗栓药物易出现出血并发症的不足,满足临床未满足的需求。
发明内容
本发明化合物为一种新型的氧代吡啶类化合物,表现出良好的抗凝血作用和对FⅪa的体内外亲和力。
一方面,本发明提供一种式(Ⅰ)所示的化合物、其立体异构体或药学上可接受的盐:
。
进一步地,上述药学上可接受的盐为金属盐。
进一步地,上述金属盐选自钠盐、钾盐、钙盐、锂盐、镁盐。
另一方面,本发明提供上述化合物、其立体异构体或药学上可接受盐的药物组合物,所述组合物还含有药学上可接受的载体和/或辅料。
再一方面,本发明提供上述化合物、其立体异构体或药学上可接受的盐的制备方法,包括如下路线:
。
另一方面,本发明还提供上述任意一项化合物、其立体异构体或药学上可接受的盐或其组合物在制备治疗和/或预防与FⅪa受体相关的疾病的药物中的应用。
进一步地,上述与FⅪa受体相关的疾病选自血栓形成或血栓栓塞相关病症。
进一步地,上述与FⅪa受体相关的疾病选自脑血管动脉疾病和/或外周动脉疾病。
进一步地,上述脑血管动脉疾病包括但不限于短暂性缺血发作(TIA)、缺血性中风或导致中风或TIA的血栓形成和/或血栓栓塞起源的事件;上述外周动脉疾病包括但不限于外周动脉闭塞、急性肢体缺血、截肢、干预(例如血管成形术、支架植入或手术和搭桥)后的再闭塞和再狭窄,和/或支架血栓形成。
进一步地,上述缺血性中风包括但不限于心源性中风、非心源性中风、由于大动脉或小动脉疾病引起的中风、由于未定原因引起的中风、隐源性中风、栓塞性中风或未定来源的栓塞性中风。
进一步地,上述心源性中风包括但不限于由于心房颤动引起的中风;上述非心源性中风包括但不限于腔隙性中风。
有益效果:本发明相对现有技术,具有很好的FXIa抑制作用,且在FeCl2诱导的兔颈动脉血栓模型中,实施例化合物1组的兔颈动血管内动脉血栓的重量相比对比例1组中兔颈动血管内动脉血栓的重量明显减少,具有统计学意义,证明本发明化合物的体内外药效显著。
具体实施方式
以下将结合实施例和实验例对本发明作进一步的详细描述,本发明的实施例和实验例仅用于说明本发明的技术方案,并非对本发明的限制,凡依照本发明公开的内容所作的任何本领域的等同置换,均属于本发明的保护范围。
化合物的结构是核磁共振(1H NMR)或液质联用(LC-MS)来确定的。
液质联用仪(LC-MS)为安捷伦G6120B(与液相Agilent 1260配用);核磁共振仪(1HNMR)为Bruker AVANCE-400或Bruker AVANCE-800,核磁共振(1H NMR)位移(δ)以百万分之一(ppm)的单位给出,内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。
本发明的术语“室温”是指温度处于10~30℃之间。
实施例1:(S)-4-(2-(4-(5-氯-2-(1H-四唑-1-基)苯基)-5-(甲氧基-d3)-2-氧嘧啶-1(2H)-基)丁酰胺基)-2-氟-N-(甲基-d3)苯甲酰胺(化合物1)的制备:
步骤1:中间体b的制备
取6-甲氧基哒嗪-3-醇(2g,15.8 mmol),加入40ml DMF溶解,加入碳酸铯(10.3g,31.6mmol),冷却至0℃,滴加氘代碘甲烷(3.5g,24.1mmol),约30分钟加完,加毕,室温搅拌反应4小时。加入EA、水,萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,柱层析提纯,得到2.1g中间体b。收率:92.84%,HPLC纯度:98.31%。
ESI-MS:m/z=144.1 (M+H)+。
步骤2:中间体c的制备
取二异丙胺(1.7g,16.8mmol)溶于20mlTHF,冷却至-60℃以下,滴加6.4ml,2.5M的正丁基锂正己烷溶液,约1小时加完,加毕,-60℃搅拌反应15分钟,滴加化合物b(2g,14.0mmol)的5ml THF溶液,用时约1小时,加毕,-60℃搅拌反应2小时,滴加硼酸三异丙酯(2.9g,15.4mmol),用时30分钟,加毕,慢慢升温至室温(20℃),搅拌反应30分钟。滴加3g醋酸和15g水的混合液,终止反应。加毕,室温搅拌30分钟。蒸出有机溶剂,加入少许水,室温搅拌15分钟,过滤,滤饼用水洗,70℃真空干燥得到2.03g固体。收率77.54%,HPLC纯度:98.54%。
ESI-MS:m/z=188.1 (M+H)+。
步骤3:中间体e的制备
取化合物d(2.59g,10.0mmol),Pd(amphos)Cl2(107.5mg,0.15mmol)悬浮于25ml叔戊醇中,加热至85℃,滴加化合物c(2.22g,11.9mmol)、碳酸钠(3.2g,30.2mmol)、25ml水的混合溶液,用时约1小时,加毕,85℃反应1小时。冷却至室温,加入EA/水萃取处理,分出水层,有机层依次用水、饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂。柱层析提纯,得到2.58g中间体e。收率80.18%,HPLC纯度:98.63%。
ESI-MS:m/z=322.1 (M+H)+。
步骤4:中间体f的制备
取化合物e(1.87g,5.80mmol)、无水氯化锂(1.3g,30.7mmol)、对甲苯磺酸一水合物(2.2g,11.6mmol)和20ml异丙醇混合,加热回流反应16小时。冷却至室温,蒸出一半溶剂,加入30ml水,室温搅拌15分钟,过滤,滤饼用水洗,70℃真空干燥,得到1.59g固体。收率:89.09%,HPLC纯度:96.37%。
ESI-MS:m/z=308.1 (M+H)+。
步骤5:中间体h的制备
25ml反应瓶加入化合物f(523mg,1.70mmol),四甲基胍(681mg,5.91mmol),异丙醇6ml,丙酮1.5ml,室温搅拌15分钟,加入化合物g(684mg,1.9mmol),室温搅拌反应过夜。次日,加入水终止反应,加入EA萃取,分出水层,有机层依次用饱和氯化铵洗,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,层析柱分离纯化,收集产物,得到857mg纯品。收率85.87%,纯度为98.69%。
ESI-MS:m/z=587.1(M+H)+。
步骤6:中间体j的制备
25ml反应瓶加入化合物h(587mg,1mmol),甲醇8ml,搅拌溶解,冷却至0℃。称取氢氧化锂一水合物(84mg,2mmol)溶于4ml水中,滴加入反应瓶,加毕,室温反应2h。加入水终止反应,5%柠檬酸调pH至弱酸性,加入EA萃取,分出水层,有机层依次用水洗,饱和NaCl洗,无水硫酸钠干燥,过滤,蒸干溶剂,柱层析,收集目标物得到419mg中间体j,收率78.92%,纯度为98.51%。
ESI-MS:m/z=531.1 (M+H)+。
步骤7:(S)-4-(2-(4-(5-氯-2-(1H-四唑-1-基)苯基)-5-(甲氧基-d3)-2-氧嘧啶-1(2H)-基)丁酰胺基)-2-氟-N-(甲基-d3)苯甲酰胺(化合物1)的制备
50ml反应瓶加入中间体j(0.3g,0.57mmol)、DMF 3ml,盐酸氘代甲胺(48.2mg,0.68mmol),EDCI(218.7mg,1.14mmol),HOBT(154mg,1.14mmol),降温至0℃,滴加入DIPEA(295mg,2.28mmol),室温反应12h,原料反应完毕。将反应液加入冷水中,乙酸乙酯萃取两次,水洗二次,饱和食盐水洗,无水硫酸钠干燥,蒸干溶剂,硅胶层析柱纯化得225mg化合物1,收率72.17%,纯度98.49%。
ESI-MS:m/z=547.2(M+H)+。
1H NMR (400 MHz, DMSO-d6) δ: 10.70 (s, 1H), 9.09 (s, 1H), 8.01 (s,1H), 7.83 – 7.66 (m, 3H), 7.71 – 7.60 (m, 2H), 7.35 (m, 1H), 7.10 (m, 1H),6.95 (s, 1H), 2.09 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H)。
对比例1:(S)-4-(2-(4-(5-氯-2-(4-(三氟甲基)-1H-1,2,3-三唑-1-基)苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰胺基)-2-氟苯甲酰胺的制备
根据专利CN108026072B中描述方法合成,纯度:98.5%。
ESI-MS:m/z=593.1(M+H)+。
1H NMR (400 MHz, DMSO-d6) δ: 10.78 (s, 1H), 9.14 (s, 1H), 7.88 – 7.77(m, 3H), 7.72 – 7.61 (m, 2H), 7.55 (d, 2H), 7.37 (dd, 1H), 7.13 (s, 1H), 6.54(s, 1H), 5.52 (dd, 1H), 3.25 (s, 3H), 2.18 – 2.00 (m, 2H), 0.78 (t, 3H)。
试验例1:对凝血因子FXIa的抑制作用
1.试验样品
实施例化合物1及对比例1。
2.试验步骤
1) 配制实验缓冲液(50mMHEPES,5mMKCl,145mMNaCl,1mg/mlPEG8000,pH7.4),平衡至室温。
2) 制备10X化合物工作液。
3) 配制0.8nM Human FXIa工作液(2X),混匀待用。
4) 加入20μL步骤3)中的FXIa工作液至384孔板(Coring,3702)所有实验孔中,200g,RT,离心10s。
5) 加入4μL步骤2)中的化合物工作液至384孔板中相应实验孔中,200g,RT,离心10s,然后将工作板置于25℃孵育20min。
6) 配制750μM S-2366工作液(2.5X),混匀待用。
7) 加入16μL步骤6)中的S-2366工作液至384孔板中所有实验孔中,200g,RT,离心10s,然后将工作板置于37℃孵育45min。
8) 孵育完成后,利用EnVision读取OD405nm 的吸收值,并收集数据。
设置5个浓度,即为:200nM、40nM、8nM、1.6nM、0.32nM,检测IC50值。
3. 数据分析
1) Z’ factor = 1-3*(SDMax+SDMin)/(MeanMax-MeanMin);
2) CVMax= (SDMax/MeanMax)*100%;
3) CVMin = (SDMin/MeanMin)*100%;
4) S/B = Singal/Background;
5) 空白对照:0.1% DMSO;阳性对照 : 对比例1;
6)IC50的计算公式: Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。
X: 化合物浓度log值; Y : Inhibition%。
4. 试验结果
试验结果见下表,结果显示:同摩尔浓度条件下,本发明的化合物,对FXIa的体外抑制活性与对比例1化合物相当。
试验例2:兔动静脉分流模型的体内药效评价
1. 试验样品
实施例化合物1及对比例1。
2.试验方法
选取新西兰白兔,全雄,30只,2.5-3.0 kg。分为3组,10只/组。分别为模型组、对比例1组和化合物1组。
对比例1组和化合物1组分别经股静脉单次注射给予6mg/kg的对比例1和化合物1所示化合物。
甲苯噻嗪(xylazine,5mg/kg)和氯胺酮(ketamine,40mg/kg)肌肉注射麻醉试验动物,并以甲苯噻嗪和氯胺酮(80mg+800mg,配制12ml)经兔右耳缘静脉(5ml/h)静脉滴注维持麻醉效果。手术暴露出一侧颈总动脉,静脉注射给药30min后,使用一片在Parafilm®条上的滤纸(10mm×10mm)缠绕颈动脉,缠绕后不影响血流,滤纸含有100μl、浓度13%的FeCl2水溶液。5min后,将滤纸移除并使用0.9%氯化钠注射液冲洗血管2次。使用滤纸30min后,切除受伤的颈动脉,取出血管内血栓并称重。
3.试验结果
如表2所示,在FeCl2诱导的兔颈动脉血栓模型中,实施例化合物1组的兔颈动血管内动脉血栓的重量相比对比例1组中兔颈动血管内动脉血栓的重量明显减少,具有统计学意义。
上述实施例仅为本发明的优选实施方式之一,不应当用于限制本发明的保护范围,但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色,其所解决的技术问题仍然与本发明一致的,均应当包含在本发明的保护范围之内。
Claims (9)
1.一种如式(I)所示的化合物、其立体异构体或药学上可接受的盐:
2.根据权利要求1所述的化合物、其立体异构体或药学上可接受的盐,其特征在于,所述盐为金属盐。
3.根据权利要求2所述的化合物、其立体异构体或药学上可接受的盐,其特征在于,所述金属盐选自钠盐、钾盐、钙盐、锂盐、镁盐。
4.一种含有权利要求1~3任意一项所述化合物、其立体异构体或药学上可接受盐的药物组合物,其特征在于,所述组合物还含有药学上可接受的载体和/或辅料。
5.权利要求1~3任意一项所述的化合物、其立体异构体或药学上可接受的盐的制备方法,其特征在于,所述方法包括如下路线:
。
6.权利要求1~3任意一项所述的化合物、其立体异构体或药学上可接受的盐或权利要求4所述的组合物在制备治疗和/或预防与FⅪa受体相关的疾病的药物中的应用。
7.如权利要求6所述的应用,其特征在于,所述与FⅪa受体相关的疾病选自血栓形成或血栓栓塞相关病症。
8.如权利要求6所述的应用,其特征在于,所述与FⅪa受体相关的疾病选自脑血管动脉疾病和/或外周动脉疾病。
9.如权利要求6所述的应用,其特征在于,所述与FⅪa受体相关的疾病选自短暂性缺血发作(TIA)或缺血性中风,包括心源性中风、例如由于心房颤动引起的中风、非心源性中风、例如腔隙性中风、由于大动脉或小动脉疾病引起的中风、或由于未定原因引起的中风、隐源性中风、栓塞性中风、未定来源的栓塞性中风,或导致中风或TIA的血栓形成和/或血栓栓塞起源的事件,和/或导致外周动脉疾病的外周动脉的病症,包括外周动脉闭塞、急性肢体缺血、截肢、干预(例如血管成形术、支架植入或手术和搭桥)后的再闭塞和再狭窄,和/或支架血栓形成。
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